Gating of steering signals through phasic modulation of reticulospinal neurons during locomotion

The neural control of movements in vertebrates is based on a set of modules, like the central pattern generator networks (CPGs) in the spinal cord coordinating locomotion. Sensory feedback is not required for the CPGs to generate the appropriate motor pattern and neither a detailed control from higher brain centers. Reticulospinal neurons in the brainstem activate the locomotor network, and the same neurons also convey signals from higher brain regions, such as turning/steering commands from the optic tectum (superior colliculus). A tonic increase in the background excitatory drive of the reticulospinal neurons would be sufficient to produce coordinated locomotor activity. However, in both vertebrates and invertebrates, descending systems are in addition phasically modulated because of feedback from the ongoing CPG activity. We use the lamprey as a model for investigating the role of this phasic modulation of the reticulospinal activity, because the brainstem–spinal cord networks are known down to the cellular level in this phylogenetically oldest extant vertebrate. We describe how the phasic modulation of reticulospinal activity from the spinal CPG ensures reliable steering/turning commands without the need for a very precise timing of on- or offset, by using a biophysically detailed large-scale (19,600 model neurons and 646,800 synapses) computational model of the lamprey brainstem–spinal cord network. To verify that the simulated neural network can control body movements, including turning, the spinal activity is fed to a mechanical model of lamprey swimming. The simulations also predict that, in contrast to reticulospinal neurons, tectal steering/turning command neurons should have minimal frequency adaptive properties, which has been confirmed experimentally.In many vertebrate and invertebrate motor systems, a phasic modulation occurs in the descending control system determining the level of activity (1–3) during rhythmic movements. The physiological role of this modulation has remained enigmatic, because it has been shown that tonic activity is sufficient to effectively drive motor activity like locomotion. One example is the reticulospinal neurons in the brainstem that serve as the major interface between higher level commands and the networks in the spinal cord in all vertebrates from lamprey to primates (4–6). In this study, we investigate the motor system of the lamprey, belonging to the most ancient group of vertebrates that has been investigated in considerable detail not only at the brainstem–spinal cord level but also with regard to the forebrain systems underlying the control of action (2, 7, 8). A bilateral symmetric activation of reticulospinal neurons will activate the locomotor networks in the spinal cord, resulting in coordinated swimming movements (2, 9–11). The reticulospinal neurons act on the excitatory and inhibitory network interneurons in the spinal cord through NMDA and AMPA receptors (12). Most reticulospinal neurons can be involved in several motor patterns (13). Whereas a bilaterally symmetric activation leads to locomotion, a unilateral addition of excitation to one side will enhance motor activity on this side and result in turning. This is the basis of steering during locomotion (14).The phasic modulation of reticulospinal neurons is most pronounced in the fastest-conducting group involved in steering (15). It results from feedback from the network neurons in the rostral segments of the spinal cord during locomotor movements, so that the reticulospinal neurons become active in phase with those segments, and during the inactive period they are instead inhibited (15–19). This feedback is conveyed to reticulospinal neurons via ascending spinobulbar neurons (15–20) that provide an “efference copy” regarding the cycle-to-cycle activity in the locomotor network. Spinobulbar neurons (21) provide the excitatory and inhibitory drive to reticulospinal neurons, resulting in modulation of their activity in phase with the ipsilateral rostral parts of the spinal cord (21, 22) and this forms a closed spino-reticulo-spinal loop (17).Visuomotor coordination (23) and steering results from activation of tectal output neurons that monosynaptically activate reticulospinal neurons (24, 25), which represent the interface between tectum and the spinal cord networks. Here, we focus on the role of the phasic modulation of the reticulospinal neurons. We show that the phasic modulation of the reticulospinal cells is advantageous in that the steering commands from tectum become gated and thereby arrive in the correct phase of the locomotor cycle. The tectal commands, therefore, need not be timed very precisely in relation to the locomotor cycle. The reticulospinal modulation ascertains that the command signal will be accurately timed provided that the tectal command signal itself remains constant and thus has a limited spike-frequency adaptation, which indeed applies to the tectal output neurons as shown here experimentally (25). We explore the effect of steering signals through a combined simulation-experimental approach. Biologically detailed lamprey spinal cell models (26) are used in large-scale simulations of the locomotor network (7) to replicate electric activity in command centers and the spinal cord. A mechanical model of swimming (27, 28) is used for a quantitative evaluation of the locomotor response.